A cruel twist of genetic fate brought Alzheimer’s disease to a sprawling Colombian family. But thanks to a second twist, one member of the clan, a woman, managed to evade the symptoms for decades. Her escape may hold the key to halting, or even preventing, Alzheimer’s.

The inherited version of Alzheimer’s disease erodes people’s memories early, starting around age 40. In this family and others, a mutation in a gene called presenilin 1 eventually leaves its carriers profoundly confused and unable to care for themselves. Locals around the Colombian city of Medellín have a name for the condition: la bobera, or “the foolishness.”

The woman in the afflicted family who somehow fended off the disease carried the same mutation that usually guarantees dementia. And her brain was filled with plaques formed by a sticky protein called amyloid. Many scientists view that accumulation as one of the earliest signs of the disease. Yet she stayed sharp until her 70s.

Researchers were stumped, until they discovered that the woman also carried another, extremely rare genetic mutation that seemed to be protecting her from the effects of the first one. This second mutation, in a different Alzheimer’s-related gene called APOE, seemed to slow the disease down by decades, says Joseph Arboleda-Velasquez, a cell biologist at Harvard Medical School.

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Genetic analyses revealed that the woman had what’s called the Christchurch mutation in both copies of her APOE gene. Further tests suggested that this mutation, named for the New Zealand city where it was first found, was shielding her from the disease. The fact that the woman had huge amounts of amyloid in her brain, yet didn’t seem impaired until her 70s, is “extremely surprising, interesting, provocative and potentially very, very informative,” Hodes says.

details in:

Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report

https://www.nature.com/articles/s41591-019-0611-3.epdf?referrer_access_token=anWKpcsTJSgWLwOHEbfZLtRgN0jAjWel9jnR3ZoTv0MD-VV86aAAyEwkkG6LIbiRdl1gDXOz3el6NPWbJcYPfu-oBopL1adg2hudWzU_eak41niIQPQZ1xbB58RkTxOEiJpz_LbEuN9HhtsOcYeYHgNV7mYjEXqtbZakzCoJLbl_Em0kdIMaD55S_21gLjP9n7nPN0W6C8SmRGBELhFXyw%3D%3D&tracking_referrer=www.sciencenews.org

 The individual had a history of dyslipidemia treated with atorvastatin 40 mg d−1. Although not previously diagnosed, the participant was confirmed to have HLP-III, including APOEch and elevated triglyceride and total cholesterol levels (Supplementary Table 4). Upon diagnosis, the atorvastatin dose was raised to 80 mg d−1 and ezetimibe 10 mg d−1 was prescribed.

 Neuroimaging measurements were used to clarify whether the subject’s resistance to clinical onset of Alzheimer’s disease was associated with relatively limited fibrillar amyloid-β plaque burden, despite more than 70 years of Aβ42 overproduction, or with relatively high amyolid-β plaque burden but limited downstream measurements of paired helical filament (PHF) tau (neurofibrillary tangle burden) and neurodegeneration.

The family in Colombia continues to help. A clinical trial testing a drug that is designed to lower amyloid is under way in Colombia.

 People who have the Paisa mutation but have not shown Alzheimer’s symptoms, as well as people without the mutation, are receiving the drug.

  The drug, crenezumab, is an antibody that’s thought to mark amyloid for destruction by immune cells. It’s being developed by Roche/Genentech.

Quiroz and her colleagues also plan to follow the Colombian woman and other members of the family over time, as part of a research exchange between Fundación Universidad de Antioquia in Medellín, which has led the studies on this family, and Massachusetts General Hospital in Boston.

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he protective effect of the woman’s mutation seems to come from an extremely specific change. In the Christchurch variant, a single spot in the APOE gene is tweaked. The resulting protein has a serine amino acid swapped in for the standard arginine.

The swap prevents the APOE protein from binding to some sugar-dotted proteins called heparan sulfate proteoglycans, or HSPGs, experiments on the isolated proteins revealed. Earlier studies showed that HSPGs may promote amyloid accumulation and nudge nerve cells to slurp up more toxic tau.

But to misbehave, HSPGs might need to partner with the APOE protein. The Christchurch mutation could have protected the woman’s brain by scrambling that nefarious relationship, the researchers suspect. Without that specific connection between APOE and HSPGs, “the disease process gets stalled,” Arboleda-Velasquez says. “This really puts a block on the cascade of events.”

Fleshing out the APOE protein’s normal biological cascade, and how that changes with the Christchurch mutation, is “going to allow for much more finely targeted drug development,” says Aisen, who also works as a consultant for Biogen, a biotechnology company in Cambridge, Mass. The company is developing an amyloid-targeting drug called aducanumab and is expected to apply for approval from the U.S. Food and Drug Administration this year (SN: 1/18/20, p. 8).

As one of the strongest genetic risk factors for dementia, the APOE gene has long been scrutinized as a possible target for Alzheimer’s drugs. People who carry a version of the gene called APOE4 have a higher risk of Alzheimer’s.

The APOE2 version dramatically lowers the risk, Quiroz, Arboleda-Velasquez and colleagues report in preliminary research posted online November 2 at medRxiv.org.

  APOE3 usually brings an average risk of Alzheimer’s, with the notable exception of the version with the Christchurch mutation carried by the Colombian woman.

Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report

We identified a PSEN1 (presenilin 1) mutation carrier from the world’s largest autosomal dominant Alzheimer’s disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer’s disease.